Abstract Inthepreviousfundingcyclewehavedemonstratedthatsyndecan?4,atransmembraneheparansulfate? carryingcoreprotein,playstwoimportantsignalingrolesinendothelialcells:regulationofAktactivityvia controlofmTORcomplex2(mTORC2)assembly,andregulationofRac1activation.BothAktandRac1arekey regulatorsofcellmigration,proliferationandsurvival.Inaddition,Aktisinvolvedinregulationof angiogenesiswhileRacplaysanimportantroleinshearstressresponseandregulationofvascular permeability.Theunexpectedinvolvementofsyndecan?4signalinginregulationofbothofthesesprocesses placesitsquarelyinthecenteroftwomajorsignalingnetworksandsuggestsanimportantroleforthisgenein keybiologicalprocesses. Instudiesoutlinedinthisapplicationweproposetoexploreindepththeroleofsyndecan?4inregulationof thesesignalingpathwaysestablishingboththemolecularbasisofsyndecan?4activityandfunctional consequencesofdisruptionofitsexpressionincludingeffectsonnormalandpathologicalangiogenesis, arteriogenesis,andvascularpermeability.Specifically,weproposethefollowingthreeAims: 1)molecularbasisofsyndecan?4dependentregulationofmTORactivity;2)Functionalsignificanceof syndecan?4?dependentregulationofmTORactivityand3)Syndecan?4dependentregulationofRac1 activation.Takentogether,thesethreeSpecificAimswillprovideacomprehensiveinsightintothesyndecan?4 roleinregulationofendothelialbiologyandproducenovelinsightsintocontrolofmTOR/AktandRac activities Project Narrative Vascular health is an important medical issue relevant to a large spectrum of cardiovascular illnesses. This projects examines a functional role of a key molecule, syndecan-4, that regulates two key aspects of vascular biology; production of nitric oxide and cell replication and migration. A better understanding of syndecan-4 biology will directly contribute to therapeutic attempts at improving vascular health and developing treatments for cardiovascular diseases.